Drug substances most frequently are administered orally by means of solid dosage forms such as tablets and capsule. Tablets may be defined as solid pharmaceutical dosage forms containing drug substances with or without suitable diluents and prepared either by compression or moulding methods. Compressed tablets usually are prepared by large-scale production methods. These tablets are formed by compression and contain no special coating. They are made from powdered, crystalline or granular materials, alone or in combination with excipients.
The most widely used and most general method of granulation used in tablet and capsule manufacture is the wet-granulation method. Its popularity is due to the greater probability that the granulation will meet all the physical requirements for the compression of good tablets. When tablet or capsule ingredients are sensitive to moisture or are unable to withstand elevated temperatures during drying, and when the tablet or capsule ingredients have sufficient inherent binding or cohesive properties, slugging may be used to form granules. This method is also referred to as dry granulation. For tablets in which the drug itself constitutes a major portion of the total tablet weight, it is necessary that the drug possess physical characteristics required for the formulation to be compressed directly. Direct Compression consists of compressing tablets directly from powdered material without modifying the physical nature of the material itself. Other related granulation processes include spheronization, spray-drying and spray congealing. The round beads in spheronization allow for better flow of material. The uniform size and spherical shape resulting material in spray-drying also improves flowability. While spray congealing allows formulators to use material best suited for adapting to prolonged release forms of the drug (Remington: The Science and Practice of Pharmacy, 19th Ed. Vol. II).
Levetiracetam of formula (I):
or (−)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide is an anticonvulsant drug and its therapeutic uses are disclosed, for example, in U.S. Pat. No. 6,903,130, U.S. Pat. No. 4,943,639 and U.S. Pat. No. 4,696,943. For example, levetiracetam is useful for the treatment of motion sickness, hyperkinesia, hypertonia, convulsive disorders, such as epilepsy, memory disorders, hypoxic and ischemic type aggressions of the CNS, bipolar disorders, mania, migraine and chronic or neuropathic pain. Levetiracetam has been produced by a variety of synthetic methods such as those described in, but not limited to, U.S. Pat. No. 4,943,639, GB 2,225,322 and U.S. Pat. No. 6,107,492.
During a wet granulation process, preparation comprises the following steps (1) blending the mixture of Active Pharmaceutical Ingredient (API) and other required pharmaceutically acceptable additives to make a uniform homogenous blend; (2) adding a wetting agent to granulate the uniform blend; (3) drying and sizing the resulting granules to an optimum size suitable for compression; (4) blending the sized granules with the required pharmaceutically acceptable additives/lubricants; and finally (5) compressing the blended granules into tablets.
Unfortunately, during development and processing of the levetiracetam, it has been observed that such processing as described above is quite sensitive, both to the amount of granulation vehicle added as well as with the drying aspect. The API, levetiracetam, in commercially available KEPPRA® tablets, generally comprises about 76% of the tablet weight. Therefore processing of the pharmaceutical blend is highly influenced by the API. For instance, during a completely Dry Granulation or Direct Compression with this compound, hardness is not attainable and the resulting tablets are friable and exhibit poor binding characteristics. Therefore granulation of any sort must involve a wet granulating agent such as water but, the active is hygroscopic and for instance is very soluble in water (104.0 g/100 ml) and therefore the quantity sprayed during mixing in a High Shear Mixer (HSM) is difficult to manage and/or optimize. When too much water is sprayed, the blend can cake and become very pasty. This pasty material then proceeds to harden in a HSM and sometimes halts the machine or impeller from further processing. Also, during the drying stage, these pasty granules will not lift in a Fluid Bed Dryer (FBD) even at maximum air velocity that is measured in Cubic Meter per Hour (CMH), since they are too heavy. As a result, the granulate takes the shape of a bowl and solidifies (into a solid block) in less than two minutes of hot or room temperature drying. Even if an alternative granulation vehicle is used, such as alcohol, and the granules do not get as drastically pasty or hard as observed with water (since the alcohol evaporates in HSM), the drying is still an issue in that the paste remains unable to lift in the FBD.